Potential role of O‐GlcNAcylation and involvement of PI3K/Akt1 pathway in the expression of oncogenic phenotypes of gastric cancer cells in vitro

Abstract

O-GlcNAcylation is a monosaccharide modification by a residue of N-acetylglucosamine (GlcNAc) attached to serine or threonine moieties on nuclear and cytoplasmic proteins. O-GlcNAcylation is dynamically regulated by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). Increasing evidence suggests that O-GlcNAcylation is involved in a variety of human cancers. However, the exact role of O-GlcNAcylation in tumor progression remains unclear. Here, we show that O-GlcNAcylation accelerates oncogenic phenotypes of gastric cancer. First, cell models with increased or decreased O-GlcNAcylation were constructed by OGT overexpression, downregulation of OGA activity with specific inhibitor Thiamet-G, or silence of OGT. MTT assays indicated that O-GlcNAcylation increased proliferation of gastric cancer cells. Soft agar assay and Transwell assays showed that O-GlcNAcylation significantly enhanced cellular colony formation, migration, and invasion in vitro. Akt1 activity was stimulated by upregulation of phosphorylation at Ser473 mediated by elevated O-GlcNAcylation. The enhanced cell invasion by Thiamet-G treatment was suppressed by PI3K inhibitor LY294002. Although the cell invasion induced by Thiamet-G was reduced by Akt1 shRNA, it was still higher in comparison with that to the control (cells with Akt1 shRNA alone). And Akt1 overexpression promoted Thiamet-G-induced cell invasion. These results suggested that O-GlcNAcylation enhanced oncogenic phenotypes possibly partially involving PI3K/Akt signaling pathway.

MiR-495 inhibits esophageal squamous cell carcinoma progression by targeting Akt1

“…Previous studies have demonstrated the major role of miRNA in the regulation of the PI3K/Akt pathway in tumor initiation and progression [18]. Here, we demonstrated that miR-495 could inhibit ESCC cell growth and metastasis in vitro and in vivo by downregulating Akt1.…”

“…To further explore the mechanisms underlying miR-495-mediated inhibition of ESCC cells ability, we examined whether miR-495 targeted Akt1. Akt1 is the crucial mediator of the PI3K/Akt signaling pathway and mediates various cellular functions in a number of tumor types, including gastric cancer [18], glioma [19], lung cancer [20], and ESCC [21]. In glioma patients, overexpression of Akt protein is correlated with later glioma grade and poor prognosis [22, 23].…”

O-GlcNAcylation and the Metabolic Shift in High-Proliferating Cells: All the Evidence Suggests that Sugars Dictate the Flux of Lipid Biogenesis in Tumor Processes

“…It would be of interest to determine whether a synergistic effect between FAS and OGT exists in lipid rafts, accentuating their respective activities. This hypothesis is supported by reports showing that, in Drosophila ( 75 ), HepG2 cells ( 72 ), MCF7 cells ( 76 ), and recently in human gastric cancer cells ( 77 ), OGT activity is crucial for activating mitogen signaling pathways.…”

GNB2L1 and its O-GlcNAcylation regulates metastasis via modulating epithelial-mesenchymal transition in the chemoresistance of gastric cancer

“…It is well-known that O-GlcNAcylation and its transferase OGT was elevated in gastric cancer and involved in the survival of gastric cancer cells [ 26 ]. And a growing amount of studies supported the critical roles of O-GlcNAcylation in gastric cancer metastasis [ 27 , 28 ]. O-GlcNAcylation not only induced the expression of matrix metalloproteinases to promote the tumour invasion, but also catalyzed EMT-related proteins to destabilize cell adhesions [ 29 – 31 ].…”